Injection molding of thermoplastic and elastomeric materials has been commonplace for several decades. Injection molding equipment has advanced from basic one-component, single cavity parts to multi-component, multi-cavity parts. For example, U.S. Pat. No. 4,376,625 discloses injection molding equipment for molding a single part from two different resins at once. Furthermore, gas-assisted plastic molding techniques have been developed to fabricate hollow parts as shown in U.S. Pat. Nos. 4,935,191 and 5,174,932. In some cases the mold cavity is pressurized in order to provide finer control for the plastic melt flow as described in U.S. Pat. No. 5,558,824. These techniques have been applied to advanced engineering problems for automotive and consumer products. For example, two-component injection molding can be used to apply a coating of virgin resin around a core of recycled, reground resin. However, co-injection techniques have not been applied to the fabrication of controlled release devices for use in controlled release of a substance to the body.
Controlled release devices deliver a specific amount of an active agent in a predictable fashion. There are several potential mechanisms for release of the active agent from the device, including, but not limited to, diffusion, osmosis, magnetism, solvent swelling, or erosion. Controlled release products have been used to deliver many different agents including, but not limited to, soaps, insecticides, and especially drugs. Substantial effort has been devoted to developing controlled release pharmaceutical dosage forms. Controlled release of pharmaceuticals encompasses a broad array of products including extended release oral dosage forms, transdermal patches, intravaginal rings (IVRs), implants, and intrauterine devices (IUDs).
Controlled release devices utilizing diffusion mechanisms form a large class of pharmaceutical dosage forms, including transdermal devices, implants and intravaginal rings. Diffusion based controlled release designs typically have a multi-laminar structure. This feature of the design frequently involves one or more rate controlling membranes or layers which surround a core reservoir containing the active chemical agent, and which function to control or moderate the rate at which the substance diffuses out of the core. A significant challenge to the manufacture of a controlled release product is the efficient application of the rate controlling membrane. Multiple step manufacturing processes are common and usually necessary to produce a device having a rate controlling membrane. Specifically, manufacturing processes for controlled release vaginal rings have included intertwined tubes described in U.S. Pat. No. 4,237,885; solvent swelling of components before assembly described in U.S. Pat. No. 4,292,965; forming an extruded tube described in U.S. Pat. No. 4,888,074; and sequential insert molding described in U.S. Pat. No. 3,920,805. All of these methods require multiple steps, and some employ hazardous solvents. The inability to efficiently manufacture vaginal rings having a rate controlling membrane surrounding a core, has been a significant reason this type of dosage form has not been widely available commercially. Therefore, methods which can reduce the number of steps required to manufacture a controlled release device, and specifically a vaginal ring, are especially valuable.
Controlled release devices provide predictable and reproducible drug release kinetic profiles for prolonged release of a therapeutic agent. The present invention provides methods for co-injection manufacture of controlled release devices having various layers or segments of materials. The methods can be utilized to mass produce products containing a variety of active agents, products having multiple layers of different polymeric materials, and products having different shapes. Two or more layers or segments are possible, and the layers or segments may contain different active agents, or be comprised only of a polymeric material. The active agent may be any agent capable of diffusing from the polymeric material. The invention may be particularly useful for controlled release of active agents such as industrial chemicals, cosmetic fragrances, growth factors, antimicrobials, metallic ions, cytotoxins, peptides, prodrugs, natural substances, cytokines, hormones, or other pharmaceutical agents.
The invention utilizes novel methods for injecting two or more materials, and thermoset materials in particular, into a mold in order to efficiently produce a controlled release device. An advantageous aspect of the invention is the ability to reliably reproduce the application of a rate controlling membrane to a core containing an active agent, whereby the device will release the agent in a predictable fashion. Materials can enter the mold through one or more gates and exit the mold through one or more runners. The materials may be sequentially injected into a mold with one or more injection nozzles or syringes. Alternatively, the materials may be simultaneously injected into the mold using a co-injection nozzle having two axially symmetric openings. The mold itself may be capable of producing more than one device in a given injection cycle by the use of multiple mold cavities. The mold design imparts the physical shape of the product, for example, a ring, a rod, or any other desired shape. However, although the mold design is important to the development of a specific product and process, various mold designs are commonplace in the art, and may be selected or adapted as desired.
In a simple embodiment, co-injection of two materials is effected by using two separate, single material injection nozzles, with a set time delay between injection of the first material and injection of the second material. A more advanced co-injection method utilizes a co-injection nozzle which provides for simultaneous, as well as sequential, entry of multiple materials into a single mold gate.
Three or more materials may be injected into a mold through a single gate. This type of flow pattern can be achieved by splitting the material feed so that more than one material is delivered by one co-injection nozzle. Instead of simply feeding material into the circular nozzle orifice from one source, there may be two sources having appropriate valving and integrated electromechanical controls such that two different materials can be sequentially fed into one orifice. Another adaptation is to split a circular orifice, for example into two semicircles.
Devices containing two or more different active agents, with a separate rate controlling membrane for each agent, may also be produced using a mold having multiple gates. Furthermore, the membrane thickness used to encapsulate each active agent may be different. In addition, the invention can be applied to shapes other than rings, for example by using a rod shaped mold.